Winship Cancer Institute of Emory University New Anticoagulants: When and Why Should I Use Them? Christine L. Kempton, MD, MSc Associate Professor of Pediatrics and Hematology and Medical Oncology Hemophilia of Georgia, Inc , Directors Chair in Hemostasis Disclosures • Nothing relevant to disclose. 1
Venous Thromboembolism (VTE) • Overall annual incidence 1/1000 persons • Increases with age: 5/1000 persons annually in people over 80 years of age • Location • Pulmonary embolism (PE) – 2/3 • Deep venous thrombosis (DVT) – 2/3 • Mortality within one month of diagnosis: • DVT – 6% • PE – 12% • Long-term complications • DVT- post-thrombotic syndrome occurs in 20-50% • PE- chronic pulmonary hypertension occurs in 2-4% Yeh et al. Blood 2014 pre-published Old Oral Anticoagulants: Warfarin • First approved for medical use in 1954 • Inhibits vitamin K reductase (VKOR) • Prevents carboxylation of clotting factors II, VII, IX, and X • Partially decarboxylated proteins have less clotting activity • Metabolised by cytochrome P450 (CYP) • particularly CYP2C9 • Limitations: • Food-drug interactions • Drug-drug interactions • Delayed onset of action • Variability of response monitoring • Safety and efficacy dependent on therapeutic INR Hirsh et al. Circulation 2003; 107: 1692-1711 2
Novel Oral Anticoagulants (NOAC) Factor XIa Factor VIIIa Factor VIIa Factor IX Factor IXa Tissue Factor Factor Va Rivaroxaban Factor X Factor Xa Apixiban Edoxaban Thrombin Dabigitran Prothrombin Fibrinogen Fibrin 4 Dabigitran Rivaroxaban Apixiban Edoxaban Target Thrombin Factor Xa Factor Xa Factor Xa Pro-drug Yes No No No Elimination 14-17 hrs 7-11 hrs 8-14 hrs 5-11 hrs half-life Bioavailability 3-7 80 66 45 % Protein 35 >90 ~85 40-59 Binding % Route of Urine ~80%, Urine ~66%, Urine ~25%, Urine ~35% elimination feces ~20% feces ~30% feces ~70% Feces ~60% Dosing Twice/day Once/day* Twice/day Once/day Substrate of No Yes (CYP3A4, Yes Yes CYP enzymes CYP2J2) (CYP3A4) (CYP3A4) Substrate of Yes Yes Yes Yes P-glycoprotein 3
Indications for Use Non- VTE Initial VTE VTE valvular prevention Treatment Secondary A. Fib Prevention Dabigitran + - + (after 5-10 days + of parenteral AC) Rivaroxaban + + + + Apixiban + + * * Edoxaban * - * (after 5-10 days of * parenteral AC) *FDA application pending Treatment of Acute VTE: Efficacy VTE Recurrence HR (95% CI) NOAC Warfarin Dabigitran- RE-COVER 2.4% 2.1% 1.10 (0.65-1.84) Study 1 ; n=1274 Rivaroxaban-EINSTEIN 2.1% 3.0% 0.68 (0.44-1.04) Study 2 ; n=3449 Rivaroxaban-EINSTEIN 2.1% 1.8% 1.12 (0.75-1.68) PE Study 3 ; n=4832 Apixiban-AMPLIFY 2.3% 2.7% 0.84 (0.60-1.18) Study 4 ; n=5244 Edoxaban-Hokusai-VTE 3.2% 3.5% 0.89 (0.70-1.13) Study 5 ; n=4921 1. Schulman et al. NEJM. 2009;361:2342-52 4. Agnelli et al. NEJM 2013; 1369:799-808 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 5. Houkusai VTE Investigators. NEJM 2013;369:1406-15 3. EINSTEIN PE Investigators NEJM 2012;366:1287-97 4
Treatment of Acute VTE: Safety Major Bleeding Clinically Relevant Non-Major Bleeding NOAC Warfarin HR NOAC Warfarin HR (95% CI) (95% CI) Dabigitran- RE-COVER 1.6% 1.9% 0.82 (0.45- 4.0% 7.8% - Study 1 ; n=1274 1.48) Rivaroxaban-EINSTEIN 1.8% 1.2% 0.65 (0.33- 7.3% 7.0% - Study 2 ; n=3449 1.30) Rivaroxaban-EINSTEIN PE 1.1% 2.2% 0.49 (0.31- 9.5% 9.8% - Study 3 ; n=4832 0.79) Apixiban-AMPLIFY study 4 ; 0.6% 1.8% 0.31* (0.17- 3.8% 8.0% 0.48 n=5244 0.55) (0.38-0.60) Edoxaban-Hokusai-VTE 1.4% 1.6% 0.84 (0.59- 8.1% 8.6% - study 5 ; n=4921 1.21) *p <0.001 4. Agnelli et al. NEJM 2013; 1369:799-808 1. Schulman et al. NEJM. 2009;361:2342-52 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 5. Houkusai VTE Investigators. NEJM 2013;369:1406-15 3. EINSTEIN PE Investigators NEJM 2012;366:1287-97 Dabigitran Apixiban Rivaroxaban Dabigitran Apixiban Rivaroxaban Dentali F, Circulation 2012;126:2381-2391 5
Secondary Prevention of VTE: Efficacy VTE Recurrence HR (95% CI) NOAC Placebo Dabigitran-RE-MEDY & 1.8% 5.6%* 0.08 (0.02-0.25) RE-SONATE 1 ; n=2856 1.3% 7.1% 0.18 (0.09-0.39) Rivaroxaban-EINSTEIN Study 2 n=1196 Apixiban-AMPLIFY EXT 3 ; 1.7%^ 8.8% 0.19 (0.11-0.33) 2.5mg n=2482 *Warfarin treated group1.3%, HR 1.44 (95% CI 0.78-2.64) ^Apixiban 2.5 mg and 5.0 mg similar 1. Schulman et al. 2013;368:709-18 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 3. Agnelli et al. NEJM 2013; 1369:799-808 Secondary Prevention of VTE: Safety Major Bleeding Clinically Relevant Non-Major Bleeding NOAC Place HR NOAC Placebo HR bo (95% CI) (95% CI) Dabigitran-RE-MEDY 0.9% 0 - 5.0% 1.8% 2.92 (1.52- 5.60) & RE-SONATE 1 ; n=2856 0.7% 0 - 5.4% 1.2% - Rivaroxaban- EINSTEIN Study 2 n=1196 Apixiban-AMPLIFY 0.2% 0.5% 0.49 (0.09- 3.0% 2.3% 1.29** 2.64) (0.72-2.33) EXT 3 ; 2.5mg n=2482 ^Apixiban 2.5 mg and 5.0 mg similar 1. Schulman et al. 2013;368:709-18 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 3. Agnelli et al. NEJM 2013; 1369:799-808 6
Agnelli et al. NEJM 2013; 1369:799-808 Patient Selection Use Avoided: Use with Caution: • PE with hemodynamic • Advanced age > 75 years instability • Extremes of weight < 60 or > • Significant risk of bleeding 150 kg • Recent trauma or surgery • CrCl < 30 ml/min • Hepatic dysfunction (Child- Pugh B) • Pregnancy • Active cancer • High-risk settings such as HIT or antiphospholipid syndrome • Concurrent use of : • Strong inhibitors/inducers of CYP3A4 and P-glycoprotein 7
Patients Currently on Warfarin INR Control Good Poor Lifestyle Adherence burden Low High Good Poor Limited benefit May benefit May benefit No benefit NOAC Selection • Preference for once daily vs. twice daily dosing: Favors rivaroxaban and edoxaban • Rivaroxaban should be taken with food • Ability to use an all oral regimen at diagnosis: Favors rivaroxaban and apixiban • Low renal clearance- Avoid dabigitran and favor apixiban • History of coronary artery disease— Avoid dabigitran • Upper GI complaints - Avoid dabigitran • Recent GI bleed- Favors apixiban • Clinical setting is extended treatment for secondary prevention— Favors apixiban • CYP3A4 interaction -Favors dabigitran 8
Monitoring • Acute Treatment: • Early follow-up if discharged from the ED • Follow-up at times of transition (apixiban: 7 days, rivaroxaban: 21 days) • Extended Treatment • Follow-up to assess adherence, efficacy, side effects, stability of renal/liver function • Every 3-12 months, depending on renal function • Laboratory monitoring • Approved kits for rivaroxaban (anti-Xa assay) and dabigitran (anti-IIa assay) • Not recommended for routine monitoring • Potential uses: • Emergent surgery or other invasive procedure • Failure of efficacy or safety • Anticipated alterations of pharmacokinetics or pharmacodynamics Practical Issues • Switching from warfarin to NOAC: • Stop warfarin and start NOAC when INR < 2.0 • Likely after 2-3 missed doses depending on the INR at cessation of warfarin • Encourage use of Medic Alert that identifies NOAC use • Discuss importance of adherence: • Use of pill box essential • Take at similar time each day • Missed dose: • < 12 hours (daily dosing) and 6 hours (BID dosing) from missed dose, then take dose • > 12 hours (daily dosing) and 6 hours (BID dosing) from missed dose—skip the dose • Do not double up 9
Bleeding Management • No reversal agent currently available, but new agents are in development Factor Xa inhibitors Direct Thrombin Inhibitors Normalization of 12-24h CrCl > 80 mL/min: 12-24h hemostasis CrCl 50-80 mL/min: 24-36h CrCl 30-50 mL/min: 36-48h CrCl < 30 mL/min: > 48h General measures Hold medication, local hemostatic measures, transfusion therapy as need for anemia and thrombocytopenia, tranexamic acid Increase clearance -- Hemodialysis Promote Prothrombin complex concentrates (PCC) (25 U/kg), hemostasis activated PCC (aPCC) (50 U/kg), or rFVIIa (90 mcg/kg)-no clinical data Heidbuchel et al. Eur Heart J 2014 pre-published Peri-operative Management • Pre-operative: Low vs. high surgical bleeding risk Dabigitran Apixiban Edoxaban Rivaroxaban Low High Low High Low High Low High CrCl > 80 mL/min > 24h > 48h > 24 h > 48h ND ND > 24 h > 48h CrCl 50-80 mL/min > 36h > 72h > 24 h > 48h ND ND > 24 h > 48h CrCl 30-50 mL/min > 72h > 120h > 24 h > 48h ND ND > 24 h > 48h ND=no data • Post-operative • Restart NOAC once full anticoagulation is allowed—likely 48-72 hours after major surgery • May need prophylactic anticoagulation with LWMH in the immediate post- operative period until able to resume full dose anticoagulation Heidbuchel et al. Eur Heart J 2014 pre-published Prescribing information 10
Summary • New oral anticoagulants … • offer a real alternative to warfarin therapy for a large number of patients. • are efficacious for: • Treatment of acute VTE: DVT and hemodynamically stable PE. • Secondary prevention of recurrent VTE. • are as safe or safer than warfarin. • are more convenient and less burdensome than warfarin. • Patients not appropriate for NOACs include those with: • Severe renal or liver impairment • Cancer • Extremes of weight • Pregnant • Significantly advanced age • Strong CYP3A4 and P-gp inhibitors 11
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